Transcriptional regulation is crucial for liver function. Both ligand-activated nuclear receptors (NRs) and orphan nuclear receptors (ONRs, NRs without known endogenous ligands) are important transcription factors to regulate gene transcription in the liver. Farnesoid X receptor (FXR) is a ligand-activated NR and bile acids are endogenous ligands of FXR. The homeostasis of bile acids is important for liver health because in addition to providing a major route for cholesterol removal bile acids also activate FXR, G-protein coupled receptor, and other signaling pathways. Emerging evidence highly supports the role of FXR in regulating broader liver homeostasis. Clearly, FXR is important for liver function because FXR deficiency in mice causes cholestasis, dyslipidemia, gallstone, hepatocellular carcinoma and diabetes. However, a major gap exists in understanding how FXR regulates transcription during liver homeostasis, which prevents us from understanding the roles of FXR in development and progression of these diseases. In order to translate FXR function in human liver physiology and diseases, it is important to determine the extent of species similarities in FXR regulation, since most studies have only been completed in mice. My hypothesis is that FXR interacts with both NRs and ONRs to regulate species-conserved pathways in the liver. My hypothesis is that ONRs facilitate chromatin modification for subsequent FXR binding and FXR interaction with HNF4&#945;is crucial in orchestrating transcription of target genes critical for liver function. This hypothesis will be tested in three specific aims. (1) Test the importance of ONRs in establishing a permissive chromatin environment for subsequent FXR binding to target genes. (2) Test the hypothesis that HNF4&#945;and FXR work together by coordinately regulating transcription of their target genes. (3) Determine similarities in FXR target genes and regulated pathways in liver of mice and humans. The proposed research is innovative in understanding transcriptional mechanism by which FXR collaborates with other transcription factors to maintain liver homeostasis. At the completion of these studies, we expect to provide a mechanism, at the chromatin level, by which liver FXR, ONRs, and HNF4 &#945; coordinately regulate gene transcription in liver. In addition, we expect to elucidate the species similarities and differences between mice and humans for the FXR target genes and regulated pathways in the liver. The species similarities will provide a scientific basis for selection of relevant translational research of FXR in human liver physiology and diseases.